Biotransformation, sometimes referred to as metabolism, is the structural modification of a chemical by enzymes in the body. Chemicals are biotransformed in several organs, including the liver, kidneys, lungs, skin, intestines, and placenta, with the liver being the most important. Chemicals absorbed in the gastrointestinal tract must pass through the liver, where they can be biotransformed and thus eliminated before being distributed to other parts of the body. This phenomenon is known as the first-pass effect. As a result, smaller amounts of certain chemicals are distributed throughout the body after oral administration than after other exposure routes, such as intravenous or intramuscular injections. Biotransformation of a chemical primarily facilitates its excretion into urine or bile; however, certain chemicals are biotransformed into more toxic forms and, as a result, biotransformation of chemicals is not always beneficial.

Biotransformation of exogenous chemicals (chemicals that are not naturally found in the body) generally occurs in two phases. In phase I, an exogenous molecule is modified by the addition of a functional group such as a hydroxyl, a carboxyl, or a sulfhydryl. This modification allows phase II, the conjugation, or joining, of the exogenous molecule with an endogenous molecule (one naturally found in the body), to take place. The major end product in most cases is a more water-soluble chemical that is easily excreted.

Phase I reactions can be classified as oxidation, reduction, or hydrolysis. Oxidation is carried out by cytochrome P-450 monooxygenases, mixed-function amine oxidases, and alcohol and aldehyde dehydrogenases. The reactions mediated by cytochrome P-450 monooxygenases can make the chemical less toxic or more toxic. The cytochrome P-450 enzymes can, for example, produce epoxides of some chemicals, which are very reactive and can attack important cellular molecules, such as DNA. The remaining phase I oxidative enzymes act on a narrow range of substrates.

In addition to the oxidation of a chemical, cytochrome P-450 monooxygenases can catalyze the reduction. Another group of enzymes that can carry out reduction is the aldehyde/ketone reductases. Each of the three groups of hydrolytic enzymes (epoxide hydrolases, esterases, and amidases, respectively) creates metabolites with a hydroxyl, carboxyl, or amino functional group.

In phase II reactions an altered exogenous chemical binds with an endogenous molecule, leading to the formation of a final product (the conjugate), which is usually much more water-soluble and easily excreted than the parent chemical. There are four types of parent compounds whose excretion can be enhanced by conjugation: glucuronic acid, glutathione, amino acids, or sulfate. The first two types are the most common phase II reactions.

Conjugation of glucuronic acid with a hydroxyl, carboxyl, amino, or sulfhydryl group leads to the formation of oxygen, nitrogen, or sulfur glucuronides, which are more easily excreted than glucuronic acid because they are more water soluble and because they contain a carboxyl group. Conjugation with glutathione also enhances excretion. Glutathione conjugation yields glutathione conjugates and mercapturic acid derivatives, which are excreted by the liver, kidney, or both.

Two types of conjugations, acetylations and methylation, do not enhance the excretion of the parent chemical. Acetylation and methylation decrease the water solubility of the parent chemical and mask the functional group of the parent chemical, preventing these functional groups from participating in conjugations that increase their excretion. Acetylation acts on chemicals with an amino group and may render them less toxic. Chemicals with an amino, hydroxyl, or sulfhydryl group can be methylated. Methylation is not as important a route of biotransformation for exogenous chemicals as it is for endogenous chemicals.

Morphological versus functional toxic responses

Chemicals can elicit various types of toxic responses, which can be classified by the nature of the response, the site of toxic action, the time it takes for the response to develop, and the chance of resolution of the response. The nature of the toxic response can be morphological (structural) or functional or both. In most cases, the chemical produces morphological changes in an organ, which in turn affects the function of the organ. In a small number of cases, the chemical produces functional changes in an organ without changing the structure of the organ.

Inhalation exposures to silica dust at a low concentration for 10 years or more can lead to chronic silicosis, a condition characterized by the formation in the lungs of silicotic nodules, which are egg-shaped lesions composed of layers of fibroblasts (reparative cells) and inflammatory cells surrounding a central silica particle. Such lesions can be considered a morphological toxic response; unless the silica exposure is prolonged, there will be little respiratory impairment because the lungs and certain other organs have a large functional reserve. If the silica exposure is prolonged, however, the silicotic nodules coalesce (complicated silicosis), and the structure of the lungs is altered so drastically that they do not distend easily during inspiration. Oxygen exchange in the alveoli is impaired, causing such functional toxic responses as breathlessness, chest tightness, and coughing with sputum.

Malathion exposure, on the other hand, can lead to functional toxic responses without causing any morphological changes. Malathion does not alter the structure of tissues; rather, it inhibits an enzyme, acetylcholinesterase, which normally degrades acetylcholine, the neurotransmitter of the parasympathetic nervous system. Inhibition of this enzyme leads to an exaggeration of the actions of the parasympathetic nervous system, including sweating, secretion of saliva, adjustment of pupil size, and defecation. The end results are increased perspiration, increased salivation, tearing, blurred vision, abdominal cramping, diarrhea, and if severe enough, death from respiratory depression.

Local versus systemic toxic responses

Toxic responses are also classified according to the site at which the response is produced. The site of toxic response can be local (at the site of first contact or portal of entry of the chemical) or systemic (produced in a tissue other than at the point of contact or portal of entry).

An example of a local toxic effect is the tissue corrosion produced by strong acids (e.g., sulfuric acid) and bases (e.g., sodium hydroxide) in contact with tissues. If the exposure is external, skin burns result; if ingested, the acid or base causes serious local damage to the esophagus and stomach.

An example of a systemic toxicant is methanol, which is absorbed and biotransformed into formic acid. The acid is responsible for metabolic acidosis and optic nerve damage in the retina of the eye, leading to visual impairment, a systemic effect.

Immediate versus delayed toxic responses

Toxic responses may also be classified according to the time it takes for development of a toxic response. If it takes up to a few days after exposure, the response is considered immediate. There is no universal standard of minimum time for delayed toxic responses, but generally a response that takes more than a few days to develop is considered delayed. The time it takes for a systemic toxicant to act depends on many factors, such as the rates of absorption, biotransformation, distribution, and excretion, as well as the speed of action at the target site.

Reversible versus irreversible toxic responses

Toxic responses differ in their eventual outcomes; the body can recover from some toxic responses, while others are irreversible. Irritation of the upper respiratory tract by inhaled formaldehyde gas, for example, is rapidly reversible in that as soon as the inhalation exposure terminates, the irritation subsides. In contrast, the response produced by silica dust is irreversible because, once the silicotic nodules are formed, they remain in the alveolar region of the lung.

Chemically induced immune responses

The immune system protects the body against foreign substances, especially microbes and viruses. To be antigenic, a substance is usually both relatively large and foreign to the body. Large proteins are often strong antigens. Smaller chemicals can become antigenic by combining with proteins in chemicals called haptens.